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Sporadic tumor mouse model for drug discovery

a mouse model and mouse technology, applied in the field of sporadic mouse model for drug discovery, can solve the problems of non-physiological levels of transgenes in the use of mouse strains as models of human cancers,

Inactive Publication Date: 2006-11-16
SCHERING CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] The present invention further provides a method for identifying a compound for treating a cancer associated with β-catenin activation comprising administering to a first β-catenin transgen

Problems solved by technology

However, the use of these mouse strains as models of human cancers suffers from several drawbacks.
Second, such strains often contain non-physiological levels of transgene due to multiple integration of the transgene.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Generation of Transgenic β-Catenin Mouse

[0049] A variation of the “hit and run” gene targeting technique (Hasty et al., Nature 350:243 (1991)) was used to produce a mouse strain containing a latent oncogenic allele of β-catenin capable of spontaneous activation in vivo. The S37F allele of β-catenin, in which the serine at residue 37 in exon 3 is replaced by phenylalanine, was chosen because it removes a major GSK3β phosphorylation site and thus stabilizes β-catenin. Mutations in the S37 codon of β-catenin have been identified in a variety of human cancers, including colorectal, hepatocellular, ovarian, uterine and thyroid (Polakis, Genes &Dev. 14:1837 (2000)).

[0050] Construction of the Targeting Vector

[0051] A 5.6-kb EcoRI-NdeI fragment of the murine β-catenin gene containing exon 2 to 7 sequences was isolated and subcloned into pSP72 (Promega, Madison, Wis.). A 1.5-kb fragment of the neomycin resistance gene was inserted into the EcoRI-ClaI restriction sites. Site directed mutag...

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Abstract

The present invention relates to a transgenic mouse containing a latent oncogenic β-catenin allele capable of spontaneous activation in vivo. The transgenic mouse is useful for the identification of compounds and immunotherapies for the prevention, treatment and / or cure of various forms of cancer associated with β-catenin activation.

Description

BACKGROUND OF THE INVENTION [0001] Beta-catenin is a key member of the highly-conserved, developmentally regulated Wnt signal transduction pathway that has been shown to play a critical role in embryonic development and oncogenic transformation (Polakis, Genes &Dev. 14:1837 (2000)). Beta-catenin plays a structural role in the assembly of cell-cell adherens junctions by forming a complex with cadherin adhesion receptors, α-catenin, and actin (Conacci-Sorrell et al., J. Clin. Invest. 109:987 (2002)). Perhaps more importantly, β-catenin can act as a transcription factor in the nucleus by serving as a coactivator of the lymphoid enhancer factor (LEF) / TCF family of DNA-binding proteins (Id.). [0002] The level of β-catenin is controlled through Wnt / wingless signaling. In the absence of Wnt signaling, a multiprotein complex including adenomatous polyposis coli (APC), axin, β-catenin and glycogen synthase kinase-3β (GSK3β) induces phosphorylation of serine and threonine residues in the amin...

Claims

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Application Information

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IPC IPC(8): A01K67/027C12N5/06
CPCA01K67/0275A01K2217/05A01K2217/072A01K2227/105C12N15/8509A01K2267/0393C07K14/4702C07K14/4705A01K2267/0331
Inventor COSTE-INVERNIZZI, ISABELLERENNO, TOUFIC
Owner SCHERING CORP
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